Bone marrow-derived mesenchymal stem cells (MSCs) are an attractive candidate for cell-mediated wound repair. Due to their plasticity, MSCs have been utilized in several preclinical and clinical trials of tissue regeneration. MSCs have been able to repair infarcted myocardium, bone, and soft tissue, albeit with varying degrees of success. These promising results are inconsistent partly due to the low levels of engraftment of MSCs within the injured tissues. Hence, strategies to increase survival and engraftment within the wound may enhance MSC therapy. We compared MSCs isolated from MRL/MpJ mice, known to demonstrate enhanced regenerative capacity, to those from C57BL/6 wild-type (WT) mice. Genomic and functional analysis indicated a down regulation of the canonical Wnt pathway in MRL-MSCs characterized by significant up-regulation of secreted frizzled-related protein 2 (sFRP2). These results led us to generate WT-MSCs overexpressing sFRP2 (sFRP2-MSCs) by retroviral transduction. sFRP2-MSCs, when implanted in vivo, resulted in enhanced engraftment, vascular density, reduced infarct size, and increased cardiac function after myocardial injury in mice. Besides increasing the proliferative index of MSCs, sFRP2 also decreased MSC apoptosis and inhibited both osteogenic and chondrogenic lineage commitment. sFRP2 activity occurred through the inhibition of both Wnt and BMP signaling pathways. We found that sFRP2-MSC-treated hearts and wound tissue had less ectopic calcification. We hypothesized that sFRP2 also increased MSC-directed wound repair by regulating their secretome and proteomic analysis of the conditioned media identified Connective Tissue Growth Factor (CTGF) to play physiological role in early wound repair. This work provides important new insight into the mechanisms by which sFRP2 increases MSC self-renewal leading to superior tissue engraftment and enhanced wound healing. These findings implicate sFRP2 as a key molecule for the biogenesis of a superior regenerative phenotype in MSCs.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03142011-094951 |
| Date | 04 April 2011 |
| Creators | Alfaro, Maria Paula |
| Contributors | Antonis Hatzopoulos, Ethan Lee, Andries Zijlstra, Larry Swift, Jeffrey M. Davidson |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03142011-094951/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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